CH685600A5 - Peptide preparations having hypocalcemic effect. - Google Patents

Description

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CH 685 600 A5

description

The present invention relates to peptides with hypocalcaemic activity (calcitonins).

As with peptides in general, the development of suitable and effective formulations for the administration of calcitonins has many problems. As peptides, calcitonins are easily broken down by gastric juices after oral administration. In addition, they pass through the mucous membranes in the body, whether in the stomach, intestine, mouth, nose or rectum, only with great difficulty and ineffectiveness (transmucosal).

The invention relates to pharmaceutical preparations containing a calcitonin as a pharmacologically active substance which has an increased hypocalcaemic effect in the blood after transmucosal administration.

In one aspect, the present invention relates to a pharmaceutical preparation containing iso-caproyl- [Ala7, Aib1 ° .17, Lys (For) 11-18, Lys (deoxyfructosyl) 24] -salmcalcitonin (5-32), which after transmucosal administration on rhesus monkeys of 5-7 kg body weight, hypocalcemic effects in the blood of at least -9%, e.g. -15%, -21% or -25%. The invention is based on the results described in the examples.

The effects are stronger than those previously published for calcitonin preparations for the same modes of administration and are therefore new. Oral administration is preferred as transmucosal administration, nasal and rectal administration are also effective.

The discovery of the strong hypocalcaemic effects enables preparations containing calcitonin to be administered transmucosal. Until now, this was not possible because of the low stability of the active compound and / or the absorption capacity of the known preparations.

In particular, the present invention relates to pharmaceutical preparations containing Isoca-proyl- [Ala7, Aib10-17, Lys (For) 11-18, Lys (deoxyfructosyl) 24] -salmcalcitonin (5-32), which when administered orally in amounts that 0.1, 0.5, 1 or 10 mg of the active ingredient correspond to hypocalcemic effects in the blood of at least -9%, for example, on a rhesus monkey of 5-7 kg body weight -15%, -21% and -25%, respectively.

The substance has the formula N-alpha-isocaproyl-Ser-Thr-AIa-Val-Leu-Aib-Lys- (For) -Leu-Ser-Gln-GIu-Leu-Aib-Lys (For) -Leu-Gln- Thr-Tyr-Pro-Lys (1-deoxy-D-fructosy!) - Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2 (For = Formyl). The formula isocaproyl- [Ala7, Aib10-17, Lys (For) 11-18, Lys (deoxyfructosyl) 24J-salmcalcito-nin (5-32) is the abbreviated form; the connection is referred to below as connection A.

Compound A and its properties are described in published UK patent application 2 218 102 A, the content of which is incorporated herein by reference. Their manufacture is described in Example 11 of this application. Compound A is indicated for use in Paget1 disease, hypercalcaemia and osteoporosis.

For use in the present invention, compound A can be in free form or in the form of a pharmaceutically acceptable salt or complex or solvate. Such salts and complexes are known and have a degree of activity and tolerance which is equivalent to the free form. Suitable acid addition salts for use according to the invention include e.g. Acetates.

The compound A differs from the known salmon calcitonin in structure and chemical properties. It is 4 amino acid residues shorter and does not have the cyclic disulfide structure that is typical of natural calcitonins.

The pharmacological profile of compound A is not the same as that of salmon calcitonin, but both compounds cause e.g. hypocalcaemic effects after injection. We have now found that Compound A is effective enough to be used in pharmaceutical preparations, e.g. for nasal administration or, if a resorption enhancer is present, additionally for oral (gastric) or rectal administration.

In another respect, the present invention relates to pharmaceutical preparations containing isocaproy! - [Ala7, Aib10-17, Lys (For) 11-18, Lys (deoxyfructosyl) 24] -salm-calcitonin (5-32) together with a bile acid or its salt, e.g. a metal or an ammonium salt, e.g. of a basic amino acid.

Bile acid or its salt promotes transmucosal absorption. The preferred bile acids are those of Formula I.

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CH 685 600 A5

CO-

I.

HO '"

R.

wherein

Ri for a- or ß-OH R2 for H or OH R3 for H or a-OH R4 for OH or

NH.R5, where R5 is -CH2COOH or -CH2-CH2-SO3H. The bile acids are known.

Preferred bile acids are those of formula I, wherein

Ri = a-OH

R2 = H

R3 = a-OH

R4 = NHRs or OH

If R5 is -CH2-COOH, the acid is glycocholic acid; when R5 is -CH2-CH2-SO3H, the acid is taurocholic acid. Other preferred acids are those in which

Ri = a- or ß-OH

If Ri = 7a-OH, then the acid is chenodeoxycholic acid; if Ri = 7ß-OH, the bile acid is ursodeoxycholic acid.

If

Ri = a-OH R2 = H

R3 = a-OH and

R4 = OH, then cholic acid is present.

The preferred bile acids are chenodeoxycholic acid and taurocholic acid. The metal salts are preferably alkali metal salts, e.g. the sodium salt.

The basic amino acids are preferably arginine, ornithine, lysine or deltahydroxylysine. Preferred acid addition salts are salts of taurocholic acid or chenodeoxycholic acid with lysine (Tauro-Lys or Cheno-Lys).

Taurocholic acid lysinate is one of the most preferred salts.

We have now found that e.g. the taurocholic acid lysinate is particularly suitable for promoting the hypocalcaemic effect of compound A.

Based on the results of Example 2 and Table I, the present invention relates in particular to a pharmaceutical preparation containing isocaproyl [Ala7, Aib10.17, Lys (For) H.i8, Lys- (deoxyfructosyl) 24] -saimcalcitonin (5-32) as an active ingredient and a bile acid which, when administered orally in an amount corresponding to 3 mg of the active ingredient, to a rhesus monkey from

R2 = H R3 = H R4 = OH

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CH 685 600 A5

5-7 kg body weight, has a relative hypocalcemic bioactivity (efficacy) of at least 200%, compared to the same preparation without bile acid, which by definition has a relative bioactivity of 100%, measured during 24 hours after the administration.

The relative hypocalcaemic effectiveness is determined by comparing the area under the curve (AUC = “area under the curve”), which indicates the hypocalcemic effect measured during 24 hours after oral administration of the preparation according to the invention and the AUC of the reference Preparation without absorption enhancer under the same conditions.

The increased hypocalcaemic effect is e.g. caused by the increased plasma level of compound A. The AUC of the plasma level can also be calculated.

10 Based on the experiments in Example 2 and the results obtained in Table II, the present invention also relates, preferably, to a pharmaceutical preparation comprising isocaproyl [Ala7, Aib10-17, Lys (For) 11-18, Lys (deoxyfructosyl) 24] salccalcitonin - (5-32) as the active ingredient and a bile acid which, when administered orally in an amount corresponding to 3 mg of the active ingredient, to a rhesus monkey of 5-7 kg body weight, a relative hypocalcaemic bioactivity (efficacy) 15 of at least 200%, compared to the same preparation without acid addition salt, which by definition has a relative bioactivity of 100%, measured during 24 hours after the administration.

The plasma level of compound A was also determined in Example 4 in a preparation additionally containing an absorption promoter after oral administration, and compared to the same preparation, but without a resorption promoter and administered intravenously. In this experiment, the absolute bioavailability is calculated.

On the basis of the results in Table III, the present invention relates to a pharmaceutical preparation comprising, as further preferred preparation, socaproyl [Ala7, Aib10-17, Lys (For) 11. "18, Lys (des-oxyfructosyl) 24] -salmcalcitonin (5 -32) as an active ingredient and a resorption promoter which, when administered orally in an amount corresponding to 200 micrograms of the active ingredient, gives Wistar rats of 280-300 g body weight an absolute bioavailability of at least 1500% in ng.h / ml, compared to the same preparation without absorption enhancer, which by definition has an absolute bioavailability of 100%, measured during 5 hours after administration.

Based on the results of Example 3, paragraph 1, it follows that compound A can be resorbed through the nose without a resorption promoter and orally with a resorption promoter, as described in Example 1.

Example 3 describes a pharmaceutical preparation which, when administered nasally in an amount corresponding to 80 micrograms of isocaproyl [Ala7, Aib10-17, Lys (For) 11.18, Lys (deoxyfructosyl) 24] -salmcalcitonin (5-32) to one Rhesus monkeys with a body weight of 5-7 kg, a relative bioavailability 35 of at least 200%, compared to a reference solution containing salmon calcitonin as an active ingredient, which by definition has a relative bioavailability of 100%, measured during 8 hours after administration.

In UK patent application 2 218 098 A it was disclosed that pharmaceutical preparations containing a salmon calcitonin and taurocholic acid lysinate have increased local tolerance 40 when administered nasally. These had a bioavailability of the same order of magnitude as those obtained by nasal administration of preparations containing salmon calcitonin and the already known absorption enhancer sodium taurocholate.

Nevertheless, based on this publication, it could not be expected that a preparation with as good hypocalcaemic activity, good tolerance and little food interaction could be obtained as that of the preparation according to the invention.

In addition, it could not be expected that good results in transmucosal penetration and bioavailability could be achieved with compound A, which is chemically very different from salmon calcitonin.

The pharmaceutical preparations can be prepared in a conventional manner, using suitable excipients depending on the mode of administration considered, e.g. oral, nasal or rectal.

The invention also relates to a process for the preparation of a pharmaceutical preparation, which is characterized in that a corresponding calcitonin is processed with auxiliaries and, if an increase in absorption is desired, e.g. for oral use of the preparation, with a bile acid or its salt, e.g. a metal salt or a basic amino acid salt. 55 These preparations are expediently prepared by customary processes and are in customary forms, e.g. as capsules, tablets, suppositories, dispersible powders, syrups, elixirs, suspensions or solutions, for e.g. enteral administration. Suitable pharmaceutical diluents or carriers are described in the examples. These can e.g. its water, lactose and suitable preservatives, suspending agents, binders, lubricants to provide an elegant and tasty pharmaceutical preparation.

If a liquid carrier is present in the nasal preparation of the invention, for example in the liquid preparation of the invention, it is preferably aqueous, but can also be selected from physiologically acceptable non-aqueous solvents which are suitable for application to the nasal mucosa. The liquid carrier is preferably water, aqueous saline, for example 65 physiological saline, or an aqueous buffer.

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If a solid support is present, i.e. in the solid nasal preparations of the invention, it can be, for example, water-insoluble, poorly water-soluble, water-absorbent, water-swellable, gel-forming or water-soluble. Examples of such carriers include, for example, synthetic or semi-synthetic polymers which are optionally crosslinked, such as polyacrylates, for example sodium, potassium 5 μm or ammonium polyacrylates, polylactic acid, polyglycolic acid, copolymers of lactic and glycolic acids, polyvinyl alcohol, polyvinyl acetate, copolymers of vinyl alcohol and acetate, carboxyvinyl polymer, polyvinyl pyrrolidone and polyethylene glycol; Celluloses such as cellulose, microcrystalline cellulose and α-cellulose, and cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and ethylhy-10 hydroxyethyl cellulose; Dextrins such as α-, β- or γ-cyclodextrin, dimethyl-β-cyclodextrin, dextrin; Starches such as native starches and their derivatives, for example hydroxyethyl or hydroxypropyl starch and carboxymethyl starch; Polysaccharides such as dextran, crosslinked dextrans, pullulan, alginic acid and its salts, hyaluronic acid and its salts, pectic acid and its salts, phytic acid and phytin; Sucrose such as D-mannitol, glucose, lactose, fructose, inositol, sucrose and amylose; Amino acids such as glycine and 15 taurine; Polyamino acids such as polyglutamic acid, polyaspartic acid, polyglycine and polyleucin; Proteins such as casein, gelatin, gelatin derivatives such as succinyl gelatin, chitin and chitosan; Gums such as gum arabic, gum tragacanth and glucomannan and phospholipids; and their mixtures. These carriers can also be present in the oral preparations of the invention. Preferred carriers are those which improve the contact of the nasal preparation with the nasal mucosa or facilitate the diffusion of the drug from the nasal preparation into the nasal mucosa, for example which prolong the residence time of the nasal preparation and / or the distance between the drug or the preparation and reduce the mucous membrane.

Preferred solid carriers are coated with polyacrylates, sodium carboxymethylceiluose, starches and their derivatives, alginic acid and its salts, hyaluronic acid and its salts, pectic acid and its salts, gelatin 25 and its derivatives, gums, polylactic acid and its copolymers, polyvinyl acetate, the celluloses and their derivatives Celluloses, cross-linked dextrans, more preferably polylactic acid and its copolymers, polyvinyl acetate, celluloses and their derivatives, coated celluloses and cross-linked dextrans. Microcrystalline cellulose is particularly preferred.

For example, for reasons of stability, the liquid preparations of the invention preferably have a slightly acidic pH, for example 3.7. The required level of acidity can be achieved in a conventional manner, for example by adding a buffering agent, or an acid such as HCl or another suitable mineral acid or organic acid, for example phosphoric acid.

Liquid and solid preparations of the invention may also contain other additives, for example antioxidants, preservatives such as benzalkonium chloride, an alkyl p-hydroxybenzoate (para-35 ben) such as methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, or sodium methyl mercurithiosalicylate (thiomersal) .

The invention further relates to a pharmaceutical preparation which is suitable for nasal administration and which contains the compound A in the absence of a resorption promoter

A promoter is understood to mean a compound which serves to increase absorption through the nasal mucosa, for example by interaction with the components of the mucous membrane and / or by increasing the permeability of the mucous membrane.

Suitable promoters include, for example, choline esters, for example the acylcarnitines disclosed in EP-A 214 898, for example the aldoses and glucosamines disclosed in EP-A 215 697, ascorbates and salicylates, for example the a-cyclodextrin disclosed in EP-A 37 943 , for example the pyroglutamate ester disclosed in EP-A 45 94 157, for example the complexing agents disclosed in EP-A 173 990, for example the polyacrylic acid base, sodium glycyrrhetinate, sodium caprate, ammonium tartrate disclosed in US Pat. No. 4,476,116 Glycyrrhizinate, for example sodium or ammonium glycyrrhizinate, for example the glycine or γ-amino-levulinic acid disclosed in EP-A 327 756.

The particle size of the components including the carrier, for example the cellulose carrier, 50 in the solid nasal preparations of the invention can be in the range from 5 to 500 μm, preferably 10 to 250 μm, in particular 20 to 200 nm.

The liquid preparations of the invention can be prepared by bringing the compound A into intimate mixture with the liquid carrier, optionally together with the other constituents.

The solid nasal preparation of the invention can be prepared in a conventional manner. Compound A can be mixed with the carrier particles, for example a polymer or a cellulose product in the usual way, optionally with other components as indicated above, e.g. a resorption enhancer or a surfactant as indicated. Compound A can be in solution, e.g. in aqueous or alcoholic solution, if it with the carrier part-60. mixed and the solvent is evaporated, e.g. by freeze drying or spray drying. Such drying can be carried out under usual conditions. Alternatively, the mixture can be compacted or granulated and then pulverized and / or sieved.

The pharmaceutical preparations of the invention are conveniently made for oral or nasal administration.

65 The exact dose of compound A, isocaproyl [Ala7, Aib10-17, Lys (For) 11'18, Lys (deoxyfructosyl) 24] -

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salmcalcitonin (5-32) can be determined in conventional animal or clinical trials. E.g. the dose can be determined by comparative bioavailability tests with other formulations with a known therapeutic effect. The dose is selected so that it delivers plasma levels of the drug in the steady state that are comparable to therapeutically effective levels.

In general, the dose of Compound A with the bile acid salt for oral or rectal administration is half to one-tenth the dose of Compound A in a comparable formulation for the same route of administration, but without an absorption promoter.

Indicated daily doses of isocaproyl [Ala7, Aib10-17, Lys (For) 11.18, Lys (deoxyf ructosyl) 24] -salmcal-citonin- (5-32) are from about 2 micrograms to about 30 mg, e.g. from 0.1 to 20 mg for oral or rectal or nasal use.

The formulations are conveniently in a single dose or they can be broken down into single dose forms containing each dose, preferably for oral use, e.g. from about 0.1 to 300 mg, preferably from 50 to 200 mg, especially up to about 100 mg of bile acid, the exact amount of e.g. depends on the mode of administration. Conveniently, the weight ratio of isocaproyl [Ala7, Aib10-17, Lys (For) 11-18, Lys (deoxyfructosyl) 24] -salmcalcitonin (5-32) to the acid addition salt of the invention is e.g. from about 1: 1 to about 1: 5000, e.g. preferably 1: 2 to 1: 2000 for oral or rectal administration.

The absorption promoter, e.g. the bile acid is e.g. used in an amount of 0.1 to 10, preferably 0.7 to 1.5% by weight as a constituent in nasal preparations, in oral and rectal preparations especially in an amount of 1 to 75 and in oral preparations in particular in an amount of 20 to 75, e.g. 40 to 75 wt .-% used.

The dose of compound A which is administered with the preparation according to the invention depends, of course, on the type of disease to be treated, the desired dose frequency and the desired result.

The invention relates in particular to a pharmaceutical preparation according to the invention for use in the treatment of Paget1 disease, hypercalcaemia or osteoporosis.

Example 1:

Capsules for oral administration

Capsules according to Example 1A containing 0.1, 0.5, 1, 2 and 10 mg of compound A and a placebo capsule are administered to each member of a group of rhesus monkeys with an approximate body weight of 5-7 kg in 6 separate experiments. The animals fasted 1 day before the treatment.

Blood ionizing calcium levels were measured after 0, 1,2, 3, 4, 5, 6, 7, 8, 12 and 24 hours.

The calcium was described with an ionizing calcium analyzer (ICA 2 radiometer) according to the method described in Selected Short Communications presented at the International Symposium «Calcitonin 1984», Milan, 2-4 October 1984, Current Clinical Practical Series 42, Exerpta Medica.

The results, shown graphically in Figure 1, show the good hypocalcaemic activity of Compound A, useful e.g. in the treatment of osteoporosis, "n" means the number of animals in the experiment.

In another experiment, the change in the total calcium content in blood in monkeys after oral administration was determined from a capsule according to Example 1A containing 1 mg of compound A and a placebo capsule.

The same experiment was carried out with capsules without taurocholic acid lysinate.

Compound A was found to have a stronger hypocalcaemic effect in the presence of taurocholic acid lysinate (Fig. 2).

The results show that pharmaceutical preparations containing isocaproylfAla7, Aib10-17, Lys- (For) 11-18, Lys (deoxyfructosyl) 24] -salmcalcitonin (5-32) when in amounts of rhesus monkeys of 5-7 kg body weight, the 0.1; 0.5; Correspond to 1 or 10 mg of the active ingredient, administered orally, a hypocalcaemic effect of -9%; -15%; Effect -21% or -25%.

The hypocalcaemic effect is the effect on the ionized calcium blood levels.

1A

mg

Compound A Taurocholic acid lysinate Microcrystalline cellulose lactose

0.1 to 20

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Example 2:

Capsules for oral administration The following preparations were compared in the manner described in Example 1.

2A mg

Compound A 3

Taurocholic acid lysinate 200

Microcrystalline cellulose 50

Magnesium stearate 25

Lactose 25

2ß mg

Compound A 3

Chenodeoxycholic Acid Lysinate 200

Microcrystalline cellulose 50

Magnesium stearate 25

Lactose 25

2Q mg

Compound A 3

Taurocholic acid lysinate 200

Microspheres thickness 50

Microcrystalline cellulose 50

Magnesium stearate 25

Lactose 25

2D mg

Compound A 3

Chenodeoxycholic Acid Lysinate 200

Microspheres thickness 50

Microcrystalline cellulose 50

Magnesium stearate 25

Placebo preparation fKapseh mg

Compound A 3

Microcrystalline cellulose 100

It has been shown that after oral administration of the preparations to rhesus monkeys, the hypocalcaemic effect after co-administration with taurocholic acid lysinate and with chenodeoxycholic acid lysinate is of the same order of magnitude. The former salt had a stronger effect. The starch microspheres in combination with both salts increase the effect somewhat, as can be seen from the numerical values in Tables I and II.

The results obtained show that the oral formulations containing taurocholic acid lysinate or chenodeoxycholic acid lysinate have relative hypocalcaemic bioactivities of 567 and 534% and

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have relative bioavailability (plasma level) of Compound A of 586 or 453% compared to the preparation of Compound A without cholic acid addition salt (placebo) (which by definition is 100%).

In these experiments, compound A plasma levels were measured using a specific RIA.

Example 3:

Nasal preparations

The hypocalcaemic effect on ionized calcium of the following preparations was measured as described in Example 1.

M ~

Spray solution Compound A Sodium chloride Benzalkonium chloride HCl 0.1N ad pH 3.7 Dest. Water N2 gas

(about 40, 400 or 800 micrograms / activation)

SB

powder

Compound A

40 micrograms

Microcrystalline cellulose

30 mg

(about 40 micrograms / capsule)

reference

Salmcalcitonin (SCT) spray solution

Salmcalcitonin (SCT) sodium chloride benzalkonium chloride HCl 0.1 N to pH 3.7 dist. Water to N2 gas approx. 40 micrograms = 200 IU / activation) placebo Sorav solution

Sodium chloride 7.5 mg

Benzalkonium chloride 0.1 mg

HCl 0.1 N ad pH 3.7 q.s.

Dest. Water 1.0 ml

N2 gas q.s.

(about 90 microliters / activation)

440 or 4400 or 8800 micrograms 7.5 mg 0.1 mg 9.5 mg 1.0 ml q.s.

440 micrograms (= 2200 I.U.)

7.5 mg

0.1 mg q.s.

1.0 ml q.s.

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1. The results obtained after administration of spray solution 3A in increasing amounts are shown graphically in FIG. 3. They show the good hypocalcaemic effect of compound A down to -21% compared to the placebo.

2. By measuring the ionized calcium of preparations 3A, 3B and the reference spray solution over 24 hours, a total bioactivity (hypocalcaemia) of 555% of preparation 3A and 760% of preparation 3B was found, in comparison with 100% of the reference solution (SCT) calculated after administration of 80 micrograms (40 micrograms in each nostril) to rhesus monkeys weighing 5-7 kg body weight.

3. By measuring the plasma level of compound A of preparations 3A and 3B and the SCT level in the reference spray solution over 8 hours, a relative bioavailability of 316% of preparation 3A and 702% of preparation 3B was compared with 100% of SCT of the reference solution, measured after administration of 80 micrograms of compound A to rhesus monkeys weighing 5-7 kg body weight.

Example 4:

Amounts of 500 microliters of saline containing 200 micrograms of Compound A either without (reference) or with a certain amount of a resorption enhancer were administered to male Wistar rats (n = 6) of 280-300 g body weight by oral intubation.

0.7 ml blood samples were taken from the jugular vein of each conscious animal 15 minutes before and 10, 30, 60, 120, 180 and 300 minutes after drug administration. All samples were analyzed using a radioimmunoassay method for salmon calcitonin after determining the cross reactivity of compound A. The active substance content is monitored by HPLC analysis.

The absolute bioavailability (BV) after oral administration was calculated according to the following equation

Medium AUC0 (0-5 hrs) (p.o.) x dose (i.v.)

BV (%) = x 100

Medium AUC0 (0-5 hrs) (IV) x dose) (PO)

certainly.

The calculated pharmacokinetic parameters are given in Table III, depending on the absorption enhancers used.

From Table III, Example 4A, it can be seen that the absolute bioavailability of Compound A with the absorption promoter is 3930%, compared to 100% of the reference preparation containing Compound A without a resorption promoter.

While the bioavailability of compound A with taurocholic acid lysinate (example 4C) is better than that with chenodeoxycholic acid lysinate (example 4B), the absorption activity of chenodeoxycholic acid in the form of the sodium salt is better in combination with lysine.HCI (example 4A).

The mixture of 1% by weight sodium chodeoxycholate with 1% lysine.HCI is theoretically equivalent to a mixture of 2.4 g moles of chenodeoxycholic acid lysinate with 3.1 g moles of lysine.HCI, which means that in comparison with Example 4B, the presence of additional Lysine has a strongly increasing influence on absorption.

It is therefore possible to increase the bioavailability of Compound A in the presence of a bile acid, regardless of whether the acid addition salt of the bile acid with the basic amino acid is present or whether both acids are present in equivalent amounts required to form an acid addition salt .

From Table III, Example 4D, it can be seen that sodium chodeoxycholate also has a beneficial effect. After oral administration, this salt can be converted to the free chenodeoxycholic acid in the acidic medium of the stomach.

In contrast to taurocholic acid, chenodeoxycholic acid is not very soluble in the acidic medium of the stomach. Compound A is released in an acidic medium from the preparation containing it, slowly if the preparation also contains chenodeoxycholic acid or its sodium salt, and more slowly than with taurocholic acid or its sodium salt.

Compound A can therefore be better protected against decomposing attacks in the acidic medium of the stomach in combination with chenodeoxycholic acid or its sodium salt than with taurocholic acid or its sodium salt.

From the protection of Compound A, chenodeoxycholic acid or its alkali metal salt is the preferred absorption enhancer for oral administration.

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Claims (16)

Claims 1. Pharmaceutical preparation containing isocaproyI [Ala7, Aib10-17, Lys (For), 11'18, Lys (deoxyfructosyi) 24] -salmcalcitonin (5-32), which after transmucosal administration to rhesus monkeys of 5-7 kg body weight has a hypocalcaemic effect in the blood of at least -9%. 2. Preparation according to claim 1 in solid form. 3. Preparation according to claim 2 containing microcrystalline cellulose. 4. Preparation according to claim 1 suitable for nasal administration. 5. Preparation containing isocaproyl [Ala7, Aib10-17, Lys (For) 11.18, Lys (deoxyfructosyl) 24] -salmcalcito-nin (5-32) and a bile acid or its salt. 6. A preparation according to claim 5, wherein the acid is taurocholic acid. 7. A preparation according to claim 5, wherein the acid is chenodeoxycholic acid. 8. A preparation according to claim 5, wherein the salt is a salt of an amino acid. 9. A preparation according to claim 8, wherein the amino acid is lysine. 10. A preparation according to claim 5, wherein the salt is a metal salt. 11. Preparation according to one of claims 1 and 5, suitable for oral administration. 12. Preparation according to one of claims 1 and 5, suitable for rectal administration. 13. Preparation suitable for nasal administration, containing isocaproyl [Ala7, Aib10-17, Lis (For) 11.18, Lys (deoxyfructosyI) 24] -salmcaicitonin- (5-32), in the absence of a resorption promoter. 14. Preparation according to claim 13 in liquid form, containing benzalkonium chloride. 15. Preparation according to one of the preceding claims, containing 2 micrograms to 30 mg of calcitonin per single dose. 16. A process for the preparation of a pharmaceutical preparation according to any one of the preceding claims, characterized in that a corresponding calcitonin is processed with auxiliaries and, if a resorption-promoting effect is desired, with a bile acid or its salt. 10th